Ophthalmic diseases such as AMD, which affect the back of the eye, particularly the retina, choroid and surrounding tissues, are very difficult to treat. Accessibility to the back of eye is one of the main reasons for this difficulty. Currently, most back of the eye or retinal/choroidal diseases are treated using intravitreal injections, which delivers a drug in the vitreous adjacent the retina. In this manner, the back of the eye is exposed to a concentration of the drug that is sufficiently high that the drug can be effective to treat a disease at the back of the eye.
Of course, intravitreal administration of drugs suffers from significant drawbacks. Patients are typically averse to having a needle penetrate into their eyes. Further, such administration of drug usually must be performed by a doctor or other trained individual, which typically requires a patient to make frequent visits to a hospital or other medical establishment to receive such administration. Both of these drawbacks can cause poor patient compliance with drug administration due scheduling problems, human avoidance and the like. Moreover, injection related risks such as endophthalmitis, retinal detachment, cataract, intraocular inflammation and others associated with the administration of intravitreal therapeutics make this route of administration less attractive.
In response to these drawbacks, the ophthalmic pharmaceutical industry has sought to provide sustained release formulations that are still provided by intravitreal administration, but which provide drug over extended periods of time. These formulations can be administered to a patient less often thereby lowering the administration burden on the patient. However, such formulations can suffer from additional risk since larger gauge needles are oftentimes used to introduce the formulations into the eye and those needles can increase multiple of the aforementioned risks associated with standard intravitreal injections.
The ophthalmic pharmaceutical industry has also sought to create drug is delivery devices that can provide sustained release and/or may be refillable. Such devices, like sustained release formulations, can lower the burden of drug administration for the patient and typically avoid the requirement of intravitreal injections. However, application of such devices often requires the performance of relatively invasive surgery and, in the case of refillable devices, the patient is typically still required to visit a hospital or other medical establishment relatively frequently.
In contrast to injections and devices, the ophthalmic pharmaceutical industry has found that topical administration of aqueous compositions is non-invasive and very convenient. However, topical administration of such compositions has been found ineffective for treatment of diseases at the back of the eye such as AMD, diabetic retinopathy and many others. The ophthalmic pharmaceutical industry has generally been unable to find drugs that, upon topical dosing, penetrate the cornea, sclera and/or conjunctiva in a manner that provides sufficient drug concentration to the back of the eye. Thus, finding a drug that will penetrate the cornea, sclera and/or conjunctiva is a significant achievement in itself. Even upon finding such a drug, however, other obstacles have prevented those drugs from being effectively formulated into topical aqueous ophthalmic compositions that can be applied to the eye safely, effectively and efficaciously. For example, it may be necessary to provide a very high concentration of drug in the composition to achieve efficacy, but such a concentration can cause side effects such as toxicity and undesirable systemic exposure. As another example, such a drug may be difficult to provide in an aqueous composition due to hydrophobicity of the drug, high reactivity of the drug with excipients commonly used in topical ophthalmic compositions or for other reasons.
Agglomeration can be particularly troublesome for the hydrophobic ophthalmic drugs discussed herein. It is known that hydrophobic drugs are particularly prone to agglomeration within aqueous topical ophthalmic compositions and such agglomeration can be particularly difficult to counteract and can cause stability and potentially other quality issues for the compositions. Moreover, it has been found that additional or alternative causes for agglomeration of drugs can be exist in an ophthalmic composition and can be particularly difficult to identify due to the expectation that agglomeration is due to hydrophobicity of the drugs. In such circumstances, the additional or alternative causes can be quite varied and unexpected making those causes particularly difficult to address.
In view of the above, it would be particularly desirable to provide an ophthalmic composition, which can be dosed topically, can provide a drug to the back of the eye at a desired concentration to treat a disease at or associated with the back of the eye and avoids problems encountered when the ophthalmic pharmaceutical industry has previously attempted to topically dose a drug to treat the back of the eye.